Transcriptional regulation of brown and beige adipocyte differentiation by EBF2

EBF2 (Early B-cell factor 2) is a transcription factor that marks committed brown and beige preadipocytes. EBF2 cooperates with PPARG, a master regulator of adipogenesis, to activate the brown/beige adipocyte thermogenic program (inferred from mouse homologs in Rajakumari et al. 2013). In white adipocytes, the activity of EBF2 is negatively regulated by binding of the transcription factor ZNF423, a key transcription factor for white adipocyte differentiation. In brown/beige fate-committed cells, the interaction between ZNF423 and EBF2 is impeded by BMP7, which acts as a positive regulator of brown/beige adipogenesis (inferred from mouse homologs in Shao et al. 2016; Shao et al. 2021). Direct transcriptional targets of EBF2 include PRDM16, UCP1, and PPARA genes. Other marker genes of brown/beige adipocytes, such as CIDEA, PPARGC1A, COX7A, and DIO2 are positively regulated by EBF2 and probably also direct targets of EBF2 (inferred from mouse homologs in Rajakumari et al. 2013; Wang et al. 2014; Stine et al. 2016; Shapira et al. 2017; Lai et al. 2017; Angueira et al. 2020). Based on mouse studies, EBF1 may function partially redundantly with EBF2 in regulation of thermogenesis genes (Angueira et al. 2020). Transcriptional activity of EBF2 is positively regulated by binding of the long noncoding RNA (lncRNA) Blnc1 (inferred from mouse homologs in Zhao et al. 2014; Mi et al. 2017). Based on mouse studies, EBF2 was reported to recruit the BAF chromatin remodeling complex to activate the transcription of target genes (Shapira et al. 2017; Liu et al. 2020). In addition to PPARG, based on mouse studies, EBF2 was reported to cooperate with other transcription factors such as SIX1 during brown/beige adipogenesis (Brunmeir et al. 2016). Besides ZNF423, based on mouse studies, other transcription factors, such as ID1 (Patil et al. 2017) and TLE3 (Pearson et al. 2019), have been reported to act as inhibitors of EBF2-mediated transcription. The transcription factor GATA6 was reported to directly stimulate EBF2 transcription during mouse beige/brown thermogenesis (Jun et al. 2023). Besides BPM7, BPM9-mediated upregulation of FGFR3 (Yamamoto et al. 2022), and FGF11 (Jiang et al. 2023) have been reported as indirect activators of EBF2 transcriptional activity in mouse and goat, respectively. ZAG (Zinc-alpha2-glycoprotein), a tumor secretory factor, has been reported to stimulate EBF2 expression, which contributes to white adipose tissue browning and energy wasting in cancer-related cachexia (Elattar et al. 2018). In the single cell atlas of human white adipose tissue (Emont et al. 2022) it was reported that the EBF2-positive hAd6 white adipocyte subpopulation with UCP1 expression, consistent with the beige profile, shows an association with increased BMI and visceral adiposity. For review, please refer to Wang and Seale 2016.

EBF2（早期B细胞因子2）是一种转录因子，标记了成熟的棕色和棕色前脂肪细胞。EBF2与PPARG（脂肪生成的主调节因子）协同作用，激活棕色/棕色脂肪细胞的产热程序（据Rajakumari等人2013年的小鼠同源物推断）。在白色脂肪细胞中，EBF2的活动受到转录因子ZNF423的负调控，ZNF423是白色脂肪细胞分化的关键转录因子。在棕色/棕色命运决定细胞中，BMP7（棕色/棕色脂肪生成的正向调节因子，据Shao等人2016年和2021年的小鼠同源物推断）阻碍了ZNF423与EBF2的相互作用。EBF2的直接转录靶标包括PRDM16、UCP1和PPARA基因。其他棕色/棕色脂肪细胞的标记基因，如CIDEA、PPARGC1A、COX7A和DIO2，受到EBF2的正向调控，并且可能是EBF2的直接靶标（据Rajakumari等人2013年、Wang等人2014年、Stine等人2016年、Shapira等人2017年、Lai等人2017年、Angueira等人2020年的小鼠同源物推断）。基于小鼠研究，EBF1可能在热生成基因的调节中与EBF2部分冗余地发挥作用（据Angueira等人2020年的研究）。EBF2的转录活性通过长非编码RNA（lncRNA）Blnc1的结合得到正向调控（据Zhao等人2014年和Mi等人2017年的小鼠同源物推断）。基于小鼠研究，EBF2被报道招募BAF染色质重塑复合体以激活目标基因的转录（据Shapira等人2017年和Liu等人2020年的研究）。除了PPARG外，基于小鼠研究，EBF2被报道在棕色/棕色脂肪生成过程中与其他转录因子如SIX1协同作用（据Brunmeir等人2016年的研究）。除了ZNF423外，基于小鼠研究，其他转录因子如ID1（据Patil等人2017年的研究）和TLE3（据Pearson等人2019年的研究）已被报道作为EBF2介导的转录的抑制剂。GATA6转录因子被报道在小鼠棕色/棕色产热期间直接刺激EBF2的转录（据Jun等人2023年的研究）。除了BPM7外，BPM9介导的FGFR3（据Yamamoto等人2022年的研究）和FGF11（据Jiang等人2023年的研究）的上调分别被报道为小鼠和山羊中EBF2转录活性间接激活因子。ZAG（锌α2-糖蛋白），一种肿瘤分泌因子，已被报道刺激EBF2的表达，这有助于癌症相关性恶病质中白色脂肪组织的棕色化和能量消耗（据Elattar等人2018年的研究）。在人类白色脂肪组织的单细胞图谱（据Emont等人2022年的研究）中，报道了EBF2阳性的hAd6白色脂肪细胞亚群与UCP1表达相关，符合棕色细胞特征，且与增加的BMI和内脏脂肪有关。欲了解更多信息，请参阅Wang和Seale 2016年的综述。